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URL Address
<a href="http://doi.org/10.1159/000493225" target="_blank" rel="noreferrer noopener">http://doi.org/10.1159/000493225</a>
Pages
932–946
Issue
3
Volume
49
Dublin Core
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Title
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Butein Activates Autophagy Through AMPK/TSC2/ULK1/mTOR Pathway to Inhibit IL-6 Expression in IL-1beta Stimulated Human Chondrocytes.
Publisher
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Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
Date
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2018
2018
Subject
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AMP-Activated Protein Kinases/metabolism; AMPK; Articular/cytology/pathology; Autophagy; Autophagy-Related Protein 5/antagonists & inhibitors/genetics/metabolism; Autophagy-Related Protein-1 Homolog/metabolism; Autophagy/*drug effects; Butein; Cartilage; Cell Survival/drug effects; Cells; Chalcones/*pharmacology; Chondrocytes/cytology/drug effects/metabolism; Cultured; Humans; Inflammation; Interleukin-1beta/*pharmacology; Interleukin-6/genetics/*metabolism; Intracellular Signaling Peptides and Proteins/metabolism; mTOR; Osteoarthritis; Osteoarthritis/metabolism/pathology; Phosphorylation/drug effects; Reactive Oxygen Species/metabolism; RNA; RNA Interference; Signal Transduction/*drug effects; Small Interfering/metabolism; TOR Serine-Threonine Kinases/metabolism; TSC2; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins/metabolism; ULK1
Creator
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Ansari Mohammad Y; Ahmad Nashrah; Haqqi Tariq M
Description
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BACKGROUND/AIMS: Butein (2',3,4,4'-Tetrahydroxychalcone), a polyphenol produced by several plants including Butea monoserpma, has been reported to exert potent anti-inflammatory activity but the mechanism remains unknown. In the present work we investigated the mechanism of Butein-mediated suppression of IL-6 expression in normal and human osteoarthritis (OA) chondrocytes under pathological conditions. METHODS: Expression level of interleukin-6 (IL-6) protein in OA cartilage was analyzed by immunohistochemistry using a validated antibody. Chondrocytes derived from normal or OA cartilage by enzymatic digestion were pretreated with Butein followed by stimulation with interleukin-1beta (IL-1beta) and the levels of IL-6 mRNA were quantified by TaqMan assay and the protein levels were measured by Western immunoblotting. Autophagy activation was determined by Western blotting and confocal microscopy. Autophagy was inhibited by siRNA mediated knockdown of ATG5. RESULTS: Expression of IL-6 protein was high in the OA cartilage compared to smooth cartilage from the same patient. OA chondrocytes and cartilage explants stimulated with IL-1beta showed high level expression of IL-6 mRNA and protein. Butein increased the phosphorylation of AMPKalphaThr-172, TSC2Ser-1387 and ULK1Ser-317 and inhibited the phosphorylation of mTORSer-2448 and its downstream target p70S6K and increased autophagy flux that correlated with the suppression of the IL-1beta mediated expression of IL-6 in normal and OA chondrocytes. In OA chondrocytes with siRNA-mediated knockdown of ATG5 expression, treatment with Butein failed to activate autophagy and abrogated the suppression of IL-1beta induced IL-6 expression. CONCLUSION: Our findings demonstrate for the first time that Butein activate autophagy in OA chondrocytes via AMPK/TSC2/ULK1/mTOR pathway. Additionally, activation of autophagy was essential to block the IL-1beta-induced expression of IL-6 in OA chondrocytes. These data support further studies to evaluate the use of Butein or compounds derived from it for the management of OA.
Identifier
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<a href="http://doi.org/10.1159/000493225" target="_blank" rel="noreferrer noopener">10.1159/000493225</a>
Rights
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
2018
Ahmad Nashrah
AMP-Activated Protein Kinases/metabolism
AMPK
Ansari Mohammad Y
Articular/cytology/pathology
Autophagy
Autophagy-Related Protein 5/antagonists & inhibitors/genetics/metabolism
Autophagy-Related Protein-1 Homolog/metabolism
Autophagy/*drug effects
Butein
Cartilage
Cell Survival/drug effects
Cells
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
Chalcones/*pharmacology
Chondrocytes/cytology/drug effects/metabolism
Cultured
Department of Anatomy & Neurobiology
Haqqi Tariq M
Humans
Inflammation
Interleukin-1beta/*pharmacology
Interleukin-6/genetics/*metabolism
Intracellular Signaling Peptides and Proteins/metabolism
mTOR
NEOMED College of Medicine
Osteoarthritis
Osteoarthritis/metabolism/pathology
Phosphorylation/drug effects
Reactive Oxygen Species/metabolism
RNA
RNA Interference
Signal Transduction/*drug effects
Small Interfering/metabolism
TOR Serine-Threonine Kinases/metabolism
TSC2
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins/metabolism
ULK1